It is known that metal ions may be attached to biological molecules by means of bifunctional chelating agents. Such chelating agents are compounds which incorporate a covalent bond-forming moiety, which may be attached to a biological molecule, and a metal-binding moiety which forms a chelate with metal ions.
In 1974 M. W. Sundberg, et al, demonstrated a seven-step synthesis yielding a bifunctional chelating agent, p-nitrophenyl EDTA. J. Med. Chem., 17, 1304 (1974). Several years later, using the seven-step synthesis of Sundberg, et al, such a para-substituted, 1-phenyl-EDTA compound was prepared, and chelates thereof were formed with .sup.111 indium. The radiolabelled chelates were demonstrated to be stable in vivo and in vitro. C. Meares, et al, Proc. Natl. Acad. Sci. U.S.A., 73, 3803 (1976). Such radiolabelled chelates may be attached to the protein human serum albumin so that the product retains biological activity, and can thus serve as a in vivo radiotracer useful in clinical or diagnostic medicine. These para-substituted, 1-phenyl EDTA compounds known to the art, although forming a variety of stable chelates, have had the disadvantage in that their synthesis has been relatively difficult.
Various other chelating agents have also been used for in vivo radiotracer studies, but have been less stable than the 1-phenyl EDTA compounds; thus, a large portion of the radioactive metal ions has tended to be lost to the serum protein transferrin. This leads to deposition of radioactive metal ions in the liver and bone marrow.
Additionally, the prior known chelating agents have normally been optically inactive: either because they do not contain an asymmetric carbon atom, or because the syntheses yield a racemic mixture. It is believed that use of non-optically active chelating agents (or racemic mixtures) with biological molecules may tend to adversely affect the in vivo properties thereof.
The present invention is directed to overcoming one or more of the problems as set forth above.